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Cell Rep. 2017 Jun 20;19(12):2557-2571. doi: 10.1016/j.celrep.2017.05.073.

OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions.

Author information

1
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40139 Bologna, Italy.
2
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
3
Medical Research Council, Mitochondrial Biology Unit, Wellcome Trust, MRC Building, Cambridge CB2 0XY, UK.
4
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy.
5
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40139 Bologna, Italy.
6
Integrated Imaging Center, Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
7
Department of Chemical Science, Life and Environmental Sustainability, University of Parma, 43124 Parma, Italy.
8
PREMMi, CNRS UMR6214, INSERM U1083, Université d'Angers, 49933 Angers Cedex 9, France.
9
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy. Electronic address: michela.rugolo@unibo.it.
10
Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40139 Bologna, Italy; IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40139 Bologna, Italy. Electronic address: valerio.carelli@unibo.it.
11
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, 40126 Bologna, Italy. Electronic address: claudia.zanna76@gmail.com.

Abstract

OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long and short forms, but it is unclear whether OPA1 functions are associated with specific isoforms and/or domains. To address this, we expressed each of the eight isoforms or different constructs of isoform 1 in Opa1-/- MEFs. We observed that any isoform could restore cristae structure, mtDNA abundance, and energetic efficiency independently of mitochondrial network morphology. Long forms supported mitochondrial fusion; short forms were better able to restore energetic efficiency. The complete rescue of mitochondrial network morphology required a balance of long and short forms of at least two isoforms, as shown by combinatorial isoform silencing and co-expression experiments. Thus, multiple OPA1 isoforms are required for mitochondrial dynamics, while any single isoform can support all other functions. These findings will be useful in designing gene therapies for patients with OPA1 haploinsufficiency.

KEYWORDS:

OPA1 isoforms; OPA1 long-short form balance; dominant optic atrophy; mitochondrial network dynamics; mtDNA

PMID:
28636943
DOI:
10.1016/j.celrep.2017.05.073
[Indexed for MEDLINE]
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